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Merck
CN
  • Modeling injury and repair in kidney organoids reveals that homologous recombination governs tubular intrinsic repair.

Modeling injury and repair in kidney organoids reveals that homologous recombination governs tubular intrinsic repair.

Science translational medicine (2022-03-03)
Navin Gupta, Takuya Matsumoto, Ken Hiratsuka, Edgar Garcia Saiz, Pierre Galichon, Tomoya Miyoshi, Koichiro Susa, Narihito Tatsumoto, Michifumi Yamashita, Ryuji Morizane
摘要

Kidneys have the capacity for intrinsic repair, preserving kidney architecture with return to a basal state after tubular injury. When injury is overwhelming or repetitive, however, that capacity is exceeded and incomplete repair results in fibrotic tissue replacing normal kidney parenchyma. Loss of nephrons correlates with reduced kidney function, which defines chronic kidney disease (CKD) and confers substantial morbidity and mortality to the worldwide population. Despite the identification of pathways involved in intrinsic repair, limited treatments for CKD exist, partly because of the limited throughput and predictivity of animal studies. Here, we showed that kidney organoids can model the transition from intrinsic to incomplete repair. Single-nuclear RNA sequencing of kidney organoids after cisplatin exposure identified 159 differentially expressed genes and 29 signal pathways in tubular cells undergoing intrinsic repair. Homology-directed repair (HDR) genes including Fanconi anemia complementation group D2 (FANCD2) and RAD51 recombinase (RAD51) were transiently up-regulated during intrinsic repair but were down-regulated in incomplete repair. Single cellular transcriptomics in mouse models of obstructive and hemodynamic kidney injury and human kidney samples of immune-mediated injury validated HDR gene up-regulation during tubular repair. Kidney biopsy samples with tubular injury and varying degrees of fibrosis confirmed loss of FANCD2 during incomplete repair. Last, we performed targeted drug screening that identified the DNA ligase IV inhibitor, SCR7, as a therapeutic candidate that rescued FANCD2/RAD51-mediated repair to prevent the progression of CKD in the cisplatin-induced organoid injury model. Our findings demonstrate the translational utility of kidney organoids to identify pathologic pathways and potential therapies.

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RAD51 Inhibitor, B02, The RAD51 Inhibitor, B02 controls the biological activity of RAD51. This small molecule/inhibitor is primarily used for Cell Structure applications.
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